ENZASTAURIN

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C32H29N5O2
Molecular Weight	515.605
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN1C=C(C2=C1C=CC=C2)C3=C(C(=O)NC3=O)C4=CN(C5CCN(CC6=CC=CC=N6)CC5)C7=C4C=CC=C7

InChI

InChIKey=AXRCEOKUDYDWLF-UHFFFAOYSA-N

InChI=1S/C32H29N5O2/c1-35-19-25(23-9-2-4-11-27(23)35)29-30(32(39)34-31(29)38)26-20-37(28-12-5-3-10-24(26)28)22-13-16-36(17-14-22)18-21-8-6-7-15-33-21/h2-12,15,19-20,22H,13-14,16-18H2,1H3,(H,34,38,39)

HIDE SMILES / InChI

Molecular Formula	C32H29N5O2
Molecular Weight	515.605
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/22879385 | https://www.ncbi.nlm.nih.gov/pubmed/16103100 | https://investor.lilly.com/releasedetail.cfm?ReleaseID=763858 | https://www.ncbi.nlm.nih.gov/pubmed/28325267

Enzastaurin is a serine/threonine kinase inhibitor that showed antiangiogenic, antiproliferative, and proapoptotic properties in vitro and antitumor activity in vivo in a xenograft Waldenström macroglobulinemia (WM) model. Enzastaurin (LY317615) is a potent PKCβ selective inhibitor. Enzastaurin suppresses angiogenesis and was advanced for clinical development based upon this antiangiogenic activity. Enzastaurin suppresses tumor growth through multiple mechanisms: direct suppression of tumor cell proliferation and the induction of tumor cell death coupled to the indirect effect of suppressing tumor-induced angiogenesis. Enzastaurin is an orally administered drug that was intended for the treatment of solid and haematological cancers. Enzastaurin had shown encouraging preclinical results for the prevention of angiogenesis, inhibition of proliferation and induction of apoptosis as well as showing limited cytotoxicity within phase I clinical trials. However, during its assessment in phase II and III clinical trials the efficacy of enzastaurin was poor both in combination with other drugs and as a single agent. Eli Lilly discontinued development of enzastaurin after top-line data from the double-blind, international Phase III PRELUDE trial in 758 DLBCL patients showed that enzastaurin missed the primary endpoint of improving DFS vs. placebo.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Protein kinase C beta 22 Target ID: CHEMBL3045 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16103100 \| https://www.ncbi.nlm.nih.gov/pubmed/12749884	Inhibitor 8504		6.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Waldenström's macroglobulinemia 7 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22879385	Primary	Phase II 1147	Unknown Approved Use Unknown
Diffuse large B-cell lymphoma 22 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28325267 https://clinicaltrials.gov/ct2/show/NCT00332202	Primary	Phase III 665	Unknown Approved Use Unknown
Glioblastoma 66 Sources: https://clinicaltrials.gov/ct2/show/NCT00295815 https://www.ncbi.nlm.nih.gov/pubmed/21896554 https://www.ncbi.nlm.nih.gov/pubmed/20124186	Primary	Phase III 665	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
1310 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16943527	700 mg 1 times / day steady-state, oral dose: 700 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		ENZASTAURIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
17400 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16943527	700 mg 1 times / day steady-state, oral dose: 700 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		ENZASTAURIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
14.4 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16943527	700 mg 1 times / day steady-state, oral dose: 700 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		ENZASTAURIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
5% EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/17671157			ENZASTAURIN plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946	inhibitor 2438

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP19A1 429 CYP2C8 1057 P-gp 1741 BCRP 910 CYP2C19 2057 CYP3A 227	CYP3A 220

Drug as perpetrator

Target	Modality	Activity
CYP19A1 430	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/743139#sid=144206918	no
BCRP 985	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/25749379/	yes
CYP2C19 2141	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/19955926/	yes
CYP2C8 1117	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/19955926/	yes
CYP2C9 2497	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/19955926/	yes
CYP3A 317	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/19955926/	yes
P-gp 1932	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/25749379/ \| https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=377020422	yes

Drug as victim

Target	Modality	Activity	Metabolite
CYP3A 220	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/16943527/	yes
CYP3A 220	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/16943527/	yes	LY326020 4
CYP3A4 1946	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/19955926/	yes

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY100444	https://www.001chemical.com/chem/search?q=DY100444
1PlusChem LLC	1P00AC0J	https://www.1pchem.com/search?query=1P00AC0J
A2B Chem	AE81331	http://a2bchem.com/prod/AE81331
AChemBlock	M15420	http://www.achemblock.com/catalogsearch/result/?q=M15420
AK Scientific	W3715	https://aksci.com/item_detail.php?cat=W3715
Alfa Chemistry	ACM359017791	http://www.alfa-chemistry.com/search.aspx?q=ACM359017791
ApexBio Technology	A1670	https://www.apexbt.com/catalogsearch/result/?q=A1670
AstaTech	43222	http://astatechinc.com/CPSResult.php?CRNO=43222
Axon MedChem	1682	https://www.axonmedchem.com/product/1682
BOC Sciences	170364-57-5	http://www.bocsci.com/description.asp?cas=170364-57-5
Capot Chemical	24445	https://www.capotchem.com/search.do?q=24445
Cayman Chemical	11601	http://www.caymanchem.com/app/template/Product.vm/catalog/11601
Chem Scene	CS-0132	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0132
ChemShuttle	104790	https://www.chemshuttle.com/catalogsearch/result/?q=104790
eMolecules	31225824	https://orderbb.emolecules.com/search/#?query=31225824
eMolecules	36745713	https://orderbb.emolecules.com/search/#?query=36745713
eNovation Chemicals	K31327	https://www.enovationchem.com/Products.asp?SEARCHTEXT=K31327&searchbtn.x=0&searchbtn.y=0
Excenen	EX-A1055	http://www.excenen.com/searchresultlist.php?id=EX-A1055
Exclusive Chemistry	2315	http://www.exchemistry.com/chem-catalog/product-2315.html
KeyOrganics	LE-0014	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=LE-0014
KeyOrganics	LE-0020	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=LE-0020
Lab Seeker	SC-85687	http://www.labseeker.com/search.php?keywords=SC-85687&category=0
LabSeeker	SC-85687	http://www.labseeker.com/search.php?keywords=SC-85687&category=0
Matrix Scientific	90588	http://www.matrixscientific.com/090588.html
mcule	MCULE-9959734001	https://mcule.com/MCULE-9959734001/
MedChem Express	HY-10342	https://www.medchemexpress.com/search.html?q=HY-10342&ft=&fa=&fp=
Molcore	MC100444	http://www.molcore.com/CatMC100444.html
Molnova	M12602	https://www.molnova.com/en/serch-list.html?keywords=M12602
MolPort	MolPort-009-194-230	https://www.molport.com/shop/molecule-link/MolPort-009-194-230
MuseChem	I002225	https://www.musechem.com/product/I002225.html
PI Chemicals	PI-38650	http://www.pipharm.com/catalog_products/PI-38650.html
Selleck Chemicals	S1055	http://www.selleckchem.com/search.html?searchDTO.searchParam=S1055
ShangHai Biochempartner	BCP000445	http://www.biochempartner.com/search_BCP000445
ShangHai Biochempartner	BCP02703	http://www.biochempartner.com/search_BCP02703
TargetMol	T6280	https://www.targetmol.com/search?keyword=T6280
Toronto Research Chemicals	A172117	https://www.trc-canada.com/product-detail/?CatNum=A172117
Toronto Research Chemicals	E560000	https://www.trc-canada.com/product-detail/?CatNum=E560000
W&J PharmaChem	50C936862	http://wjpharmachem.com/new/searcht.php?keyword=50C936862

PubMed

Title	Date	PubMed
Hypoxia, tumor endothelium, and targets for therapy.	2005	16594131
The protein kinase Cbeta-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts.	2005 Aug 15	16103100
Perspectives in central nervous system malignancies.	2006 Jun	16752310
Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer.	2006 Sep 1	16943527
Inorganic pyrophosphate generation by transforming growth factor-beta-1 is mainly dependent on ANK induction by Ras/Raf-1/extracellular signal-regulated kinase pathways in chondrocytes.	2007	18034874
Survival improvement in thoracic cancer: progress from the last decade and beyond.	2007 Aug	17686443
Phase I pharmacokinetic and pharmacodynamic study of the oral protein kinase C beta-inhibitor enzastaurin in combination with gemcitabine and cisplatin in patients with advanced cancer.	2007 Aug 1	17671132
Role of anti-angiogenesis agents in treating NSCLC: focus on bevacizumab and VEGFR tyrosine kinase inhibitors.	2007 Feb	17634832
Safety, tolerability, QTc evaluation, and pharmacokinetics of single and multiple doses of enzastaurin HCl (LY317615), a protein kinase C-beta inhibitor, in healthy subjects.	2007 Sep	17766700
Chemoradiotherapy in malignant glioma: standard of care and future directions.	2007 Sep 10	17827463
Systemic treatment for advanced (stage IIIb/IV) non-small cell lung cancer: more treatment options; more things to consider. Conclusion.	2008	18263773
Protein kinase C isozymes as therapeutic targets for treatment of human cancers.	2008	18167314
Enzastaurin inhibits tumours sensitive and resistant to anti-EGFR drugs.	2008 Aug 5	18665191
A phase I safety, tolerability, and pharmacokinetic study of enzastaurin combined with capecitabine in patients with advanced solid tumors.	2008 Jan	18043132
Targeted treatment and new agents in diffuse large B-cell lymphoma.	2008 Jul	18760704
The oral protein-kinase C beta inhibitor enzastaurin (LY317615) suppresses signalling through the AKT pathway, inhibits proliferation and induces apoptosis in multiple myeloma cell lines.	2008 Jul	18452078
[Protein kinases C: a new cytoplasmic target].	2008 Jul-Aug	18755647
Enzastaurin renders MCF-7 breast cancer cells sensitive to radiation through reversal of radiation-induced activation of protein kinase C.	2008 Jun	18448327
Involvement of protein kinase C beta-extracellular signal-regulating kinase 1/2/p38 mitogen-activated protein kinase-heat shock protein 27 activation in hepatocellular carcinoma cell motility and invasion.	2008 Mar	18167130
[Recent therapeutic progress in non-Hodgkin lymphoma: focusing on diffuse large B-cell lymphoma and follicular lymphoma].	2008 Oct	18833928
Novel therapies in breast cancer: what is new from ASCO 2008.	2008 Oct 1	18828924
Molecular pathways involved in the synergistic interaction of the PKC beta inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells.	2008 Sep 2	18728666
The heat shock protein antagonist 17-AAG potentiates the activity of enzastaurin against malignant human glioma cells.	2008 Sep 8	18462865
Design of Phase II cancer trials for evaluation of cytostatic/cytotoxic agents.	2009	19384693
Targeting PKC: a novel role for beta-catenin in ER stress and apoptotic signaling.	2009 Feb 12	19018094
Antiangiogenic drugs in ovarian cancer.	2009 Jan 13	19002176
[Role of PKCbeta in the malignant tumors and enzastaurin, a PKCbeta inhibitor].	2009 May	19618717
A phase I trial of enzastaurin in patients with recurrent gliomas.	2009 May 15	19417015
Conformationally constrained analogues of diacylglycerol (DAG). 31. Modulation of the biological properties of diacylgycerol lactones (DAG-lactones) containing rigid-rod acyl groups separated from the core lactone by spacer units of different lengths.	2009 May 28	19379015
Recruitment of PKC-betaII to lipid rafts mediates apoptosis-resistance in chronic lymphocytic leukemia expressing ZAP-70.	2010 Jan	19907441
Protein kinase Cbeta modulates ligand-induced cell surface death receptor accumulation: a mechanistic basis for enzastaurin-death ligand synergy.	2010 Jan 8	19887445

Patents

Sample Use Guides

In Vivo Use Guide

1125 mg loading dose then 500 mg, oral, daily, until disease progression or maximum of 3 years

Route of Administration: Oral

In Vitro Use Guide

In the BON1 cell line Enzastaurin inhibited cell proliferation at 5 and 10 uM by inducing caspase-mediated apoptosis, and reduced phosphorylation of glycogen synthetase kinase 3β (GSK3β) and of Akt, both downstream targets of PKC pathway and pharmacodynamic markers for Enzastaurin.

Substance Class	Chemical Created by `admin` on `Mon Mar 31 18:26:16 GMT 2025` Edited by `admin` on `Mon Mar 31 18:26:16 GMT 2025`
Record UNII	UC96G28EQF
Record Status	`Validated (UNII)`
Record Version

Download

Name

Type

Language

ENZASTAURIN

Official Name

English

LY-317615

Preferred Name

English

ENZASTAURIN [MI]

Common Name

English

Enzastaurin [WHO-DD]

Common Name

English

LY317615

Code

English

3-(1-METHYL-1H-INDOL-3-YL)-4-(1-(1-(PYRIDIN-2-YLMETHYL)PIPERIDIN-4-YL)-1H-INDOL-3-YL)-1H-PYRROLE-2,5-DIONE

Systematic Name

English

enzastaurin [INN]

Common Name

English

1H-PYRROLE-2,5-DIONE, 3-(1-METHYL-1H-INDOL-3-YL)-4-(1-(1-(2-PYRIDINYLMETHYL)-4-PIPERIDINYL)-1H-INDOL-3-YL)-

Systematic Name

English

DB-102

Code

English

ENZASTAURIN [USAN]

Common Name

English

DB102

Code

English

Classification Tree Code System Code

FDA ORPHAN DRUG

849821